This invention relates to methods of increasing bone mass in humans and other animals, i.e., for the treatment of osteoporosis and related bone metabolic disorders. In particular, this invention relates to such methods of treatment by the administration of a bone-active phosphonate and parathyroid hormone.
The most common metabolic bone disorder is osteoporosis. Osteoporosis can be generally defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue. In general, there are two types of osteoporosis: primary and secondary. "Secondary osteoporosis" is the result of an identifiable disease process or agent. However, approximately 90% of all osteoporosis cases is "primary osteoporosis". Such primary osteoporosis includes postmenopausal osteoporosis, age-associated osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis affecting middle-aged and younger men and women.
For some osteoporotic individuals the loss of bone tissue is sufficiently great so as to cause mechanical failure of the bone structure. Bone fractures often occur, for example, in the hip and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.
The mechanism of bone loss in osteoporotics is believed to involve an imbalance in the process of "bone remodeling". Bone remodeling occurs throughout life, renewing the skeleton and maintaining the strength of bone. This remodeling involves the erosion and filling of discrete sites on the surface of bones, by an organized group of cells called "basic multicellular units" or "BMUs". BMUs primarily consist of "osteoclasts", "osteoblasts", and their cellular precursors. In the remodeling cycle, bone is resorbed at the site of an "activated" BMU by an osteoclast, forming a resorption cavity. This cavity is then filled with bone by osteoblasts.
Normally, in adults, the remodeling cycle results in a small deficit in bone, due to incomplete filling of the bone resorption cavity. Thus, even in healthy adults, age-related bone loss occurs. However, in osteoporotics, there is an increase in the number of BMUs that are activated. This increased activation accelerates bone remodeling, resulting in abnormally high bone loss.
Although its etiology is not fully understood, there are many risk factors thought to be associated with osteoporosis. These include low body weight, low calcium intake, physical inactivity, and estrogen deficiency.
Many compositions and methods are described in the medical literature for the "treatment" of osteoporosis. Many of these compositions and methods attempt to either slow the loss of bone or to produce a net gain in bone mass. See, for example, R. C. Haynes, Jr. et al., "Agents affecting Calcification", The Pharmacological Basis of Therapeutics, 7th Edition (A. G. Gilman, L. S. Goodman et al., Editors, 1985); G. D. Whedon et al., "An Analysis of Current Concepts and Research Interest in Osteoporosis", Current Advances in Skeletogenesis (A. Ornoy et al., Editors, 1985); and W. A. Peck, et al., Physician's Resource Manual on Osteoporosis (1987), published by the National Osteoporosis Foundation.
Among the treatments for osteoporosis suggested in the literature is the administration of bisphosphonates or other bone-active phosphonates. See, for example, Storm et al., "Effect of Intermittent Cyclical Etidronate Therapy on Bone Mineralization and Fracture Rate in Women with Post-Menopausal Osteoporosis", 322 New England Journal of Medicine 1265 (1990); and Watts et al., "Intermittent Cyclical Etidronate Treatment of Post-Menopausal Osteoporosis", 323 New England Journal of Medicine 73 (1990). Such treatments using a variety of bisphosphonates are described in U.S. Pat. No. 4,761,406, Flora et al., issued Aug. 2, 1988; U.S. Pat. No. 4,812,304, Anderson et al., issued Mar. 14, 1989; U.S. Pat. No. 4,812,311, Uchtman, issued Mar. 14, 1989; and U.S. Pat. No. 4,822,609, Flora, issued Apr. 18, 1989. The use of such phosphonates for the treatment of osteoporosis, and other disorders involving abnormal calcium and phosphate metabolism, is also described in U.S. Pat. No. 3,683,080, Francis, issued Aug. 8, 1972; U.S. Pat. No. 4,330,537, Francis, issued Oct. 28, 1980; U.S. Pat. No. 4,267,108, Blum et al., issued May 12, 1981; European Patent Publication 298,553, Ebetino, published Jan. 11, 1989; and Francis et al., "Chemical, Biochemical, and Medicinal Properties of the Diphosphonates", The Role of Phosphonates in Living Systems, Chapter 4 (1983).
Parathyroid hormone has also been suggested as a therapy for osteoporosis. Such treatments using parathyroid hormone are disclosed in the following references, Hefti, et al., "Increase of Whole-Body Calcium and Skeletal Mass in Normal and Osteoporotic Adult Rats Treated with Parathyroid Hormone", 62 Clin. Sci. 389-396 (1982), German Patent Publication DE 39 35 738, Forssman, published May 8, 1991, U.S. Pat. No. 4,698,328, Neer, et al., issued Oct. 6, 1987, and U.S. Pat. No. 4,833,125, Neer, et al., issued May 23, 1989.
The effects of administering a bisphosphonate and a parathyroid hormone was studied in rats. The study concluded that bone mass increased more in rats treated with a bisphosphonate and parathyroid hormone than in rats treated solely with parathyroid hormone. See Hock, et al., "Resorption Is Not Essential for the Stimulation of Bone Growth by hPTH-(1-34) in Rats In Vivo", 4(3) Jnl. of Bone and Mineral Res. 449-458 (1989).
Cyclic administration of parathyroid hormone and bone-active phosphonates has been suggested as a therapy for osteoporosis in humans. Such treatments using bisphosphonates and parathyroid hormone are disclosed in the following references, all hereby incorporated by reference herein, U.S. Pat. No. 4,822,609, Flora, issued Apr. 18, 1989; U.S. Pat. No. 4,812,304, Anderson, et al., issued Mar. 14, 1989; German Patent Publication DE 32 43 358, Hesch, published May 24, 1984 and; Hesch, et al., "Results of a Stimulating Therapy of Low Bone Metabolism in Osteoporosis with (1-38h PTH and Diphosphonate EHDP" 66(19) Klin. Wschr. 976-984 (October 1988).
Additionally, the short term use of parathyroid hormone and bone-active phosphonates has been described in the following references: German Patent Publication DE 32 43 358, Hesch, published May 24, 1984 (hereinaftter "DE 32 43 358"); Hesch, et al., "Results of a Stimulatory Therapy of Low Bone Metabolism in Osteoporosis with (1-38)hPTH and Diphosphonate EHDP" 66(19) Klin. Wschr. 976-984 (October 1988) (hereinafter "Hesch, et al."); Delling, et al., "Morphologic Study of Pelvic Crest Spongiosa in Patients with Osteoporosis during ADFR Therapy with Parathyroid Hormone and Diphosphonates", 128(1) Z. Orthop. 1-5 (1990) (hereinafter "Delling, et al "); and Delmas, et al., "The In Vivo Anabolic Effect of hPTH-(1-34) Is Blunted When Bone Resorption Is Blocked By A Bisphosphonate" 6(1) J. Bone Mineral Res. S136 (#214) (August 1991) (hereinafter "Delmas").
However, the methods described in DE 32 43 358, and Hesch, et al., and Delling, et al., while useful in activating bone metabolism, have not been shown to be effective in increasing bone mass. Delling, et al. is especially skeptical of the effectiveness of a parathyroid hormone/bisphosphonate therapy for increasing bone mass. Delling, et al. conclude that a significant change in bone structure was not observed and that the utility of such a therapy is questionable. Delmas, is also skeptical of the effectiveness of parathyroid hormone and bisphosphonate therapy since his data indicate that parathyroid hormone is effective in increasing bone formation by itself but when administered in conjunction with a bisphosphonate the combination is less effective than the control (i.e. no treatment) in increasing bone formation.
Applicant has found, surprisingly, that the administration of bone-active phosphonates and parathyroid hormone increases bone mass. Accordingly, the methods of this invention provide effective methods of preventing and treating osteoporosis, with reduced side effects compared to such methods known in the art.